Nitric Oxide (NO) bioactivity is reduced in the coronary and systemic circulations of patients with coronary artery disease (CAD). Our purpose was to determine whether L-arginine, the substrate for NO synthesis, improves homeostatic functions of the vascular endothelium in patients with CAD mantained on appropriate medical management, and thus might be useful adjunctive therapy in the management of their disease. Thirty patients (29 men, average age 67+/-8 years) with CAD and stable symptoms on appropriate medical management participated in this study. Testing was performed after 1 month of L-arginine 9 gm or placebo, with crossover to the alternate therapy after 1 month off therapy in a randomized, double-blind study. Nitrogen oxides in serum were measured (chemiluminescence technique)on a nitrate-restricted diet as an index of endothelial NO release, brachial artery flow-mediated dilation was measured by ultrasound following forearm ischemia as an index of endothelial NO bioactivity, and soluble cell adhesion molecules were measured in serum as an index of NO-regulated inflammatory markers. Compared with placebo, L-arginine therapy increased plasma levels of L-arginine (mean+/-SD: 130+/-53 vs. 70+/-17 micromol/L, P=0.0001). However, there were no significant differences in serum nitrogen oxides (19.3+/-7.9 vs. 18.6+/-6.7 micromol/L, P=0.55), flow-mediated dilation (11.9+/-6.3 vs.11.4+/-7.9%, P=0.74), or serum levels of E-selectin (47.8+/-15.2 vs. 47.2+/-14.4 ng/mL, P=0.60), intercellular adhesion molecule-1 (250+/-57 vs. 249+/-57 ng/mL, P=0.86), and vascular cell adhesion molecule-1 (567+/-124 vs. 574+/-135 ng/mL, P=0.47). We conclude that oral L-arginine therapy may not augment endothelial NO release or bioactivity in CAD patients on appropriate medical management. Accordingly, this therapeutic approach may not be of atheroprotective benefit to this group of patients. - L- arginine, nitric oxide, endothelium-dependent, chemiluminescence technique - Human Subjects